PyRx – Python Prescription

I’ve added instructions on how to update to the latest version from Source Code and how to submit a feature equest to Downloads page. The major new feature in 0.5 is database table plotting feature that can be used for BioAssays and ROC Curves. To compare ROC curves generated by two different docking algorithms, I run the dataset from my previous blog post through AutoDock Vina. There are third party packages available for AutoDock Vina such as PaDEL-ADV, VcPpt, MakeVinaCommand and PyMOL plugin. The new version of ADT also has features for working with output files generated by Vina. To explore an option for adding a new Wizard to PyRx for AutoDock Vina, I run AutoDock Vina on our cluster, using a script from Vina Manual. Here are the results:

This is just a proof of concept to show that you can use PyRx to analyse results from different docking programmes.

I’ve got an email from My NCBI about new BioAssay – Limit: Protein 3D Structure. AID: 2158 has Compounds Active: 287; Tested: 572; it’s exaclty that I was looking for. Based on this data, I’ve implemented new features that will available in upcoming 0.5 release. Interested users can check it out right away. The new feature allows you to plot Binding Energies to provide a bird’s-eye view of docking results. In addition, if you have corresponding BioAssay available, you can also plot ROC Curve next to Docking Results. ROC curves appear in many recent publications that prompted me to add this feature to PyRx. Google search on ROC Curve brought me to Receiver operating characteristic – Wikipedia. This page confused me more than it helped me, so I started searching for ROC curve further. I came across Let’s ROC that had the following article mentioned in the comments: Triballeau, N. et al. J Med Chem. 2005, 48, 2534-2547. This article is very well written and it helped me to better understand the use of ROC curves in Virtual Screenings.

This plot shows Docking Results and ROC Curve generated for AID: 2158 BioAssay. Note that results with lowest Binding Energy, as predicted by AutoDock, are active compounds. It might seem that overall AutoDock doesn’t do well because some of the points on ROC curve are below the diagonal. However, this all depends on the dataset chosen. If the dataset had only a few active compounds, then chances are, that it would have produced an ideal ROC curve. In that sence, ROC curve, by itself, is not informative, unless you have a plot of Docking Results like the way PyRx does.

I started searching PubChem BioAssays and limited results to the ones that link to Protein 3D Structure. There are currently only 61 BioAssays available. I wanted to select a BioAssay that would have around 100 compounds tested, but only handful that are active. In order to test PyRx and see what new features to add, I have been working with qHTS Assay for Promiscuous and Specific Inhibitors of Cruzain (with detergent) (AID: 1478). There were 617 compounds with the 3D records and I selected 1ME4 as a target for docking. After reading corresponding references from PubChem BioAssay and PDB, I prepared input pdbqt files for ligands and macromolecule. Since there were more that 6 ligand atom types, I needed AutoDock version 4.2 or higher. Luckily there is new Autodock4.2.1 service available.To make PyRx aware of this new service, I’ve added a new page for AutoDock Preferences, where users can change the name of the service, should a new version of AutoDock become available.

I’ve also made the following changes that will be available in the upcoming release of PyRx:

• Modified Remote Jobs Query in webSerives; it now updates the GUI after checking each job individually.
• Made changes to AutoDockPage to make parsing and displaying docking results faster.

You can access the latest version of the code from https://sourceforge.net/projects/pyrx/develop.

As a side note, I was trying to find PubChem Compound ID (CID) for T10. PubChem’s Chemical structure search did not recognize InChI provided by PDB. Fortunately, InChI Resolver from ChemSpider was able to read InChI from PDB (ChemSpider ID:  4451401) and I was able to find correpsonding PubChem ID (CID 5289424). It turns out that InChI versions in PDB and PubChem are not the same. It would be nice if there would be a link in Ligand Summary page that PDB displays that would point to a PubChem ID, whenever corresponding ligand is available in PubChem.

I’ve got a green light from our Office of Technology Development to distribute PyRx under Open Source BSD License. For users, this means that you are free to use PyRx for academic as well as commercial purposes. For potential developers, this means that you can now contribute code to PyRx. I’ve created a project for PyRx at http://sourceforge.net/projects/pyrx and you are welcome to join the project. Visit https://sourceforge.net/projects/pyrx/develop for more information.

I’m happy to announce that PyRx has made into Chemical & Engineering News. Please refer to the following publication if you’d like to cite PyRx in your article:

• L.K. Wolf, C&EN 87, 31 (2009)

Also, I’ll be presenting PyRx during Virtual Screening & Computer Aided Drug Design training session at the Summer Institute organized by National Biomedical Computation Resource (NBCR). Here is a link to the outline titled Getting Started with PyRx.

The following are list of changes in PyRx version 0.5 and earlier:

Version 0.5 – 25 March 2010

• Added Save as Comma-Separated Values (CSV) tool for database tables.
• Added plotting feature for database tables. This feature can be accessed through a toolbar button under Tables tab. By default, it opens up Table Plotting Dialog where a bar plot of Binding Energy versus Ligand (index) is shown. If you have PubChem BioAssay opened using open CVS button, this widget will also check to see if there is Outcome column in that table, and if so, it will color bars corresponding to “Active” compound red and bars corresponding to “Inactive” blue.
• Changed default for maximum number of energy evaluations (generic algorithm parameter in AutoDock) from medium (ga_num_evals = 2500000) to short (ga_num_evals = 250000).
• Added AutoDock PBS job submission progress dialog.
• Fixed a bug that was causing problems when displaying molecular surfaces for docked conformations.
• Added a dialog to select alternate conformation when making macromolecule file (pdbqt) for AutoDock.
• Enabled Enthought’s quality agent that can be used to get bug report and comments from a user.
• Added Cancel option for AutoGrid Web Services.
• Implemented flexible residues for AutoDock. This feature can be accesses by selecting residue(s) under Navigator -> Molecules and right-clicking on them. Select AutoDock -> Flexible Residues to create _flex folder under Navigator -> AutoDock -> Macromolecules with receptor pdbqt and flex.pdbqt. All docking to this receptor is then done with this flexible residue(s).
• Updated Python to version 2.6 and ETS to 3.4.0.
• The new installers delete previous installation folder, if any, before installing this new version.

Version 0.4 – 2 November 2009

• Fixed TraitError: The ‘cpu_num’ (see Re: PyRx won’t start).
• Added AutoDockRemotePreferencesPage to allows users to change AutoDock and AutoDock service names. The defaults are set to Autodock_4.2.1 and Autodock_4.2.1.
• Modified Remote Jobs Query in webSerives; it now updates the GUI after checking each job individually.
• Made changes to AutoDockPage to make parsing and displaying docking results faster.
• PyRx Table is populated when user clicks on that tab to speed up the startup time (see Re: How can I find the mistake).

Version 0.3 – 23 September 2009

• When making AutoDock Ligands using Open Babel, it now logs problem causing cases.
• Fixed Maximize action for Run AutoGrid page on AutoDock Wizard.
• Local AutoDock executable paths can now have spaces in it.
• Added splash screen.
• Updated Enthought Tool Suite to version 3.3.0.

Version 0.2 – 20 June 2009

• Addition of Molecular Surfaces Using IsoSurface.
• Upgraded AutoDockTools to version 1.5.4.
• Modified default Mouse Picking provided by Mayavi keyboard interactions. Pressing ‘p’ key now displays the full name and coordinates of the atom under the cursor.

Version 0.1 – 23 April 2009

• Fixed a couple of critical bugs including the one mentioned here.
• Upgraded Enthought Tool Suite to version 3.0.2 and Open Babel to 2.2.1.
• Added new AutoDock Execution Mode labeled Cluster (Portable Batch System) mode.

Molecular Libraries that are available from PubChem or elsewhere, usually contain 2D structures generated from molecular formulas or SMILES strings. To prepare these files for docking, PyRx is using OpenBabel to parse Structured Data Format (SDF). TableEditor from enthought.traits allows users to sort/filter molecules. The results are displayed in TVTK scene as sticks and balls. PyRx also provides options to run energy minimization for selected or all molecules. Energy minimization is done using OpenBabel and we have a GUI that can be used to change energy minimization parameters.

Finally, PyRx has menus for converting selected or all molecules to AutoDock Ligand format (PDBQT). Users have options for removing fragments smaller that specific number (OpenBable.StripSalts) and an option to choose partial charges (OpenBabel or PyBabel from MGLTools).

When all input structures are ready for docking, start Virtual Screening by using AutoDock Wizard widget shown below.

On the first page select whether to run AutoDock locally or remotely (buzzword: cloud computing) using Opal Web Services Toolkit developed at National Biomedical Computation Resource (http://nbcr.net). The advantage of using Web Services over PBS Batch Job is that Web Services can be run from Windows or Mac OS X based PC, whereas PBS Batch Job require Unix/Linux cluster. On “Select Ligands” and “Select Macromolecule” page user selects ligands and macromolecule, correspondingly, from the list of available molecules in Navigator pane.

On “Run AutoGrid” page adjust grid box by dragging handles of the VTK box widget before running AutoGrid.

On “Run AutoDock” page user can select among four docking algorithms available in AutoDock 4.0 as well as modify docking parameters used in each algorithm.

“Analyze Results” page is presented at the end of Virtual Screening where binding energies are displayed. Users can sort/filter results or save them as CSV (comma-separated values) for further analysis with third-party spreadsheet programs.. We also provide option for plotting clustering histograms using matplotlib – python 2D plotting library. “Analyze Results” page can also be used to open DLGs (docking log files) from previous AutoDock runs.